Sensitivity to intravenous nicotine in smokers: genetic moderators Abstract: Smoking is an important public health problem costing over 430,000 lives a year in the U.S. alone. The biological mechanisms contributing to nicotine reward have not been well elucidated in humans. Increasing evidence suggests that mu opioid receptors (MOR) likely contribute to the rewarding effect of nicotine as well as sex differences in nicotine reward. Further, a functional polymorphism in the MOR gene (OPRM1), A118G (Asn40Asp), has been associated with rewarding effects of alcohol in alcohol users and nicotine in female smokers. The proposed study will extend these previous findings by evaluating the OPRM1 A118G polymorphism in male and female smokers as a moderator of the subjective-rewarding effects of intravenous (IV) nicotine. The IV nicotine administration procedure that we have developed shows promise for evaluation of genetic moderators of nicotine sensitivity in both male and female smokers. As an exploratory aim, we will also evaluate the influence of rs16969968 SNP at the 15 nicotinic cholinergic receptor gene (CHRNA5). Since, variation at this SNP, G398A, seems to enhance responses to nicotinic agonist in vitro, it is of interest to evaluate its effects on nicotine responses in humans. The proposed study is expected to fill a critical gap in our understanding of genetic factors moderating dose-dependent rewarding effects of nicotine. By providing a better understanding of biological mechanisms of nicotine reward, this study may contribute to development of more effective treatments for smoking cessation. PUBLIC HEALTH RELEVANCE: Smoking is an important public health problem costing over 430,000 lives a year in the U.S. alone. This proposed study will seek to determine the genetic factor moderating nicotine's rewarding effects. By providing a better understanding of biological mechanisms of nicotine reward, this study may contribute to development of more effective treatments for smoking cessation.